5-179345258-GGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_014244.5(ADAMTS2):c.68_70dupTGC(p.Leu23dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,134,850 control chromosomes in the GnomAD database, including 8,203 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2398 hom., cov: 28)

Exomes 𝑓: 0.14 ( 5805 hom. )

Consequence

ADAMTS2
NM_014244.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.00

Publications

6 publications found

Variant links:

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS2 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, dermatosparaxis type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 5-179345258-G-GGCA is Benign according to our data. Variant chr5-179345258-G-GGCA is described in ClinVar as [Benign]. Clinvar id is 353147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 link	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 11		NP_067610.1	O95450-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 link	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 link	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 link	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.68_70dupTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

25853

AN:

146894

Hom.:

2397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0918

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.319

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.128

Gnomad NFE

AF:

0.139

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.159

AC:

177

AN:

1116

AF XY:

0.168

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.400

Gnomad FIN exome

AF:

0.151

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.138

AC:

136367

AN:

987864

Hom.:

5805

Cov.:

AF XY:

0.138

AC XY:

65035

AN XY:

471428

show subpopulations

African (AFR)

AF:

0.193

AC:

3666

AN:

18992

American (AMR)

AF:

0.143

AC:

784

AN:

5482

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

1198

AN:

9706

East Asian (EAS)

AF:

0.300

AC:

4735

AN:

15772

South Asian (SAS)

AF:

0.259

AC:

4877

AN:

18822

European-Finnish (FIN)

AF:

0.191

AC:

2911

AN:

15242

Middle Eastern (MID)

AF:

0.143

AC:

350

AN:

2440

European-Non Finnish (NFE)

AF:

0.130

AC:

112364

AN:

864644

Other (OTH)

AF:

0.149

AC:

5482

AN:

36764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5405

10810

16216

21621

27026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5170

10340

15510

20680

25850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.176

AC:

25877

AN:

146986

Hom.:

2398

Cov.:

AF XY:

0.184

AC XY:

13156

AN XY:

71614

show subpopulations

African (AFR)

AF:

0.207

AC:

8286

AN:

40028

American (AMR)

AF:

0.163

AC:

2431

AN:

14926

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

463

AN:

3404

East Asian (EAS)

AF:

0.319

AC:

1578

AN:

4942

South Asian (SAS)

AF:

0.291

AC:

1388

AN:

4776

European-Finnish (FIN)

AF:

0.221

AC:

2062

AN:

9312

Middle Eastern (MID)

AF:

0.121

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.139

AC:

9228

AN:

66362

Other (OTH)

AF:

0.158

AC:

325

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1021

2042

3062

4083

5104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0421

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

South Asian population allele frequency is 25.41% (rs193247334, 38/112 alleles, 8 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ADAMTS2 c.68_70dupTGC (p.Leu23dup) results in an in-frame insertion that is predicted to insert one amino acid into the encoded protein. The variant allele was found at a frequency of 0.17 in 28092 control chromosomes in the gnomAD database, including 419 homozygotes. The observed variant frequency is approximately 60-fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.68_70dupTGC in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Sep 26, 2018

GeneDx

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

- -

Jun 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=72/28

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over